My immediate career goal is to establish a patient-oriented research program on Parkinson's disease (PD) while completing a Master of Public Health. My long-term goal is to apply my various skills in clinical neurology, experimental pharmacology, and epidemiological research to address questions regarding the interactions between the environment and genetics in the development of neurological disease. I anticipate doing this in an academic environment with the opportunity for ongoing and close collaboration between disciplines, as represented in this proposal. The focus of my intermediate career goals is understanding the etiology of PD. Evidence suggests that PD results from an interaction between environmental exposures to particular toxins and genetic factors that act as effect modifiers or independent risk factors. Current efforts to understand these interactions rely on the combined techniques of analytic epidemiology and molecular biology. This proposal will couple these approaches with clinical neurological assessment in order to elucidate these interactions. The first aim is to use a population-based, case-control study of PD to evaluate genetic polymorphisms as possible effect modifiers of environmental exposures. DNA samples will be analyzed for genetic polymorphisms related to dopamine and xenobiotic metabolism (MAO- B, CYP-2D6 and 2E1, PON1, and GST isoenzymes Ml, T1, and P1). The second aim will extend this ongoing study to include cases of drug-induced parkinsonism (DIP), based on the hypothesis that if these cases represent a group of especially susceptible patients, they may harbor genetic polymorphisms of interest. The third aim will be to use an ongoing longitudinal, cohort study of orchardists evaluating the association of parkinsonism with historic, chronic pesticide exposures. In this work I will utilize my previous training in clinical neurology to provide increased internal validity and decrease the effect of disease misclassification. As well, models to refine individual exposure assessments will be developed and applied to historic data in order to decrease the effect of exposure misclassification. The fourth aim will be to evaluate the role of the alpha-7 nicotinic receptor as a risk factor for PD. I will benefit from direct mentoring by national leaders in the fields of Environmental Health and Epidemiology (Dr. Checkoway), Neurology (Dr. Longstreth), and Occupational Medicine (Dr. Keifer). My aims will extend and augment the ongoing, multidisciplinary investigation of PD risk factors, while providing me an unparalleled opportunity to develop my career in the rich, scientific milieu of the University of Washington.